CA2007507C - Sphingosine et n-methyl-sphingosine inhibiteurs de la croissance des cellules - Google Patents

Sphingosine et n-methyl-sphingosine inhibiteurs de la croissance des cellules

Info

Publication number: CA2007507C
Authority: CA; Canada
Prior art keywords: sphingosine; prepared; pharmaceutically acceptable; medicament; acceptable salts
Prior art date: 1989-02-03
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Expired - Fee Related

Application number

CA002007507A

Other languages

English (en)

Other versions

CA2007507A1 (fr

Inventor

Yasuyuki Igarashi

Tatsushi Toyokuni

Sen-Itiroh Hakomori

Efraim Racker

Shuji Fujita

Mamoru Sugimoto

Masayoshi Ito

Yoshiyasu Shitori

Tomoya Ogawa

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Mect Corp

Cornell Research Foundation Inc

Biomembrane Institute

Original Assignee

Mect Corp

Cornell Research Foundation Inc

Biomembrane Institute

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1989-02-03

Filing date

1990-01-10

Publication date

1998-05-19

1990-01-10 Application filed by Mect Corp, Cornell Research Foundation Inc, Biomembrane Institute filed Critical Mect Corp

1990-08-03 Publication of CA2007507A1 publication Critical patent/CA2007507A1/fr

1998-05-19 Application granted granted Critical

1998-05-19 Publication of CA2007507C publication Critical patent/CA2007507C/fr

2010-01-10 Anticipated expiration legal-status Critical

Status Expired - Fee Related legal-status Critical Current

Links

WWUZIQQURGPMPG-KRWOKUGFSA-N sphingosine Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)CO WWUZIQQURGPMPG-KRWOKUGFSA-N 0.000 title claims abstract description 128
WWUZIQQURGPMPG-UHFFFAOYSA-N (-)-D-erythro-Sphingosine Natural products CCCCCCCCCCCCCC=CC(O)C(N)CO WWUZIQQURGPMPG-UHFFFAOYSA-N 0.000 title claims abstract description 120
PTGGMPLMNDBPGB-CXISOLTFSA-N n-[(e,2s,3r)-1,3-dihydroxyoctadec-4-en-2-yl]formamide Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@H](CO)NC=O PTGGMPLMNDBPGB-CXISOLTFSA-N 0.000 title claims abstract description 100
230000010261 cell growth Effects 0.000 title claims abstract description 71
239000003112 inhibitor Substances 0.000 title description 10
230000002401 inhibitory effect Effects 0.000 claims abstract description 150
150000003408 sphingolipids Chemical class 0.000 claims abstract description 148
239000003966 growth inhibitor Substances 0.000 claims abstract description 126
239000003814 drug Substances 0.000 claims abstract description 105
150000003839 salts Chemical class 0.000 claims abstract description 104
230000012010 growth Effects 0.000 claims abstract description 51
210000004027 cell Anatomy 0.000 claims abstract description 40
239000003085 diluting agent Substances 0.000 claims abstract description 33
239000003937 drug carrier Substances 0.000 claims abstract description 33
239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 31
238000001727 in vivo Methods 0.000 claims abstract description 20
210000004102 animal cell Anatomy 0.000 claims abstract description 16
210000005260 human cell Anatomy 0.000 claims abstract description 16
206010028980 Neoplasm Diseases 0.000 claims description 86
YRXOQXUDKDCXME-YIVRLKKSSA-N N,N-dimethylsphingosine Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@H](CO)N(C)C YRXOQXUDKDCXME-YIVRLKKSSA-N 0.000 claims description 83
210000004698 lymphocyte Anatomy 0.000 claims description 77
241001465754 Metazoa Species 0.000 claims description 58
230000028993 immune response Effects 0.000 claims description 35
230000028709 inflammatory response Effects 0.000 claims description 27
108010062580 Concanavalin A Proteins 0.000 claims description 23
210000003714 granulocyte Anatomy 0.000 claims description 22
230000006472 autoimmune response Effects 0.000 claims description 20
230000003211 malignant effect Effects 0.000 claims description 18
108010047620 Phytohemagglutinins Proteins 0.000 claims description 16
230000001885 phytohemagglutinin Effects 0.000 claims description 16
108010002350 Interleukin-2 Proteins 0.000 claims description 12
241000124008 Mammalia Species 0.000 claims description 12
210000004881 tumor cell Anatomy 0.000 claims description 12
206010027476 Metastases Diseases 0.000 claims description 10
230000001419 dependent effect Effects 0.000 claims description 10
230000009401 metastasis Effects 0.000 claims description 10
210000001744 T-lymphocyte Anatomy 0.000 claims description 6
210000004962 mammalian cell Anatomy 0.000 claims description 6
230000002757 inflammatory effect Effects 0.000 claims description 4
230000001363 autoimmune Effects 0.000 claims 1
238000000034 method Methods 0.000 abstract description 39
230000000694 effects Effects 0.000 description 24
230000005764 inhibitory process Effects 0.000 description 24
BLTCBVOJNNKFKC-QUDYQQOWSA-N N-acetylsphingosine Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@H](CO)NC(C)=O BLTCBVOJNNKFKC-QUDYQQOWSA-N 0.000 description 15
150000003410 sphingosines Chemical class 0.000 description 15
WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 12
241000699666 Mus <mouse, genus> Species 0.000 description 12
CRJGESKKUOMBCT-VQTJNVASSA-N N-acetylsphinganine Chemical compound CCCCCCCCCCCCCCC[C@@H](O)[C@H](CO)NC(C)=O CRJGESKKUOMBCT-VQTJNVASSA-N 0.000 description 11
229940106189 ceramide Drugs 0.000 description 11
YDNKGFDKKRUKPY-JHOUSYSJSA-N C16 ceramide Natural products CCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)C=CCCCCCCCCCCCCC YDNKGFDKKRUKPY-JHOUSYSJSA-N 0.000 description 10
ZVEQCJWYRWKARO-UHFFFAOYSA-N ceramide Natural products CCCCCCCCCCCCCCC(O)C(=O)NC(CO)C(O)C=CCCC=C(C)CCCCCCCCC ZVEQCJWYRWKARO-UHFFFAOYSA-N 0.000 description 10
VVGIYYKRAMHVLU-UHFFFAOYSA-N newbouldiamide Natural products CCCCCCCCCCCCCCCCCCCC(O)C(O)C(O)C(CO)NC(=O)CCCCCCCCCCCCCCCCC VVGIYYKRAMHVLU-UHFFFAOYSA-N 0.000 description 10
210000004988 splenocyte Anatomy 0.000 description 10
102000000588 Interleukin-2 Human genes 0.000 description 8
210000005104 human peripheral blood lymphocyte Anatomy 0.000 description 8
206010009944 Colon cancer Diseases 0.000 description 7
241000699660 Mus musculus Species 0.000 description 7
208000029742 colonic neoplasm Diseases 0.000 description 7
150000001875 compounds Chemical class 0.000 description 7
238000011580 nude mouse model Methods 0.000 description 7
238000011282 treatment Methods 0.000 description 7
JSPNNZKWADNWHI-PNANGNLXSA-N (2r)-2-hydroxy-n-[(2s,3r,4e,8e)-3-hydroxy-9-methyl-1-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoctadeca-4,8-dien-2-yl]heptadecanamide Chemical compound CCCCCCCCCCCCCCC[C@@H](O)C(=O)N[C@H]([C@H](O)\C=C\CC\C=C(/C)CCCCCCCCC)CO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O JSPNNZKWADNWHI-PNANGNLXSA-N 0.000 description 6
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
229930183167 cerebroside Natural products 0.000 description 6
RIZIAUKTHDLMQX-UHFFFAOYSA-N cerebroside D Natural products CCCCCCCCCCCCCCCCC(O)C(=O)NC(C(O)C=CCCC=C(C)CCCCCCCCC)COC1OC(CO)C(O)C(O)C1O RIZIAUKTHDLMQX-UHFFFAOYSA-N 0.000 description 6
102000001253 Protein Kinase Human genes 0.000 description 5
IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 5
239000002609 medium Substances 0.000 description 5
108060006633 protein kinase Proteins 0.000 description 5
102000001301 EGF receptor Human genes 0.000 description 4
108060006698 EGF receptor Proteins 0.000 description 4
WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
210000004369 blood Anatomy 0.000 description 4
239000008280 blood Substances 0.000 description 4
LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 4
150000002270 gangliosides Chemical class 0.000 description 4
150000002632 lipids Chemical class 0.000 description 4
238000006140 methanolysis reaction Methods 0.000 description 4
239000002953 phosphate buffered saline Substances 0.000 description 4
238000011160 research Methods 0.000 description 4
239000012279 sodium borohydride Substances 0.000 description 4
229910000033 sodium borohydride Inorganic materials 0.000 description 4
QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 3
102000004201 Ceramidases Human genes 0.000 description 3
108090000751 Ceramidases Proteins 0.000 description 3
230000006820 DNA synthesis Effects 0.000 description 3
KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 3
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
125000003047 N-acetyl group Chemical group 0.000 description 3
230000015572 biosynthetic process Effects 0.000 description 3
210000004556 brain Anatomy 0.000 description 3
239000000872 buffer Substances 0.000 description 3
DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 3
238000004128 high performance liquid chromatography Methods 0.000 description 3
238000000338 in vitro Methods 0.000 description 3
238000007069 methylation reaction Methods 0.000 description 3
239000000203 mixture Substances 0.000 description 3
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
210000005105 peripheral blood lymphocyte Anatomy 0.000 description 3
210000002975 pon Anatomy 0.000 description 3
238000004611 spectroscopical analysis Methods 0.000 description 3
238000003786 synthesis reaction Methods 0.000 description 3
MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 2
AFSHUZFNMVJNKX-CLFAGFIQSA-N 1,2-dioleoylglycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(CO)OC(=O)CCCCCCC\C=C/CCCCCCCC AFSHUZFNMVJNKX-CLFAGFIQSA-N 0.000 description 2
TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 description 2
238000005160 1H NMR spectroscopy Methods 0.000 description 2
108091003079 Bovine Serum Albumin Proteins 0.000 description 2
ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 description 2
102000005744 Glycoside Hydrolases Human genes 0.000 description 2
108010031186 Glycoside Hydrolases Proteins 0.000 description 2
238000005481 NMR spectroscopy Methods 0.000 description 2
102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 2
108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 2
239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 2
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
229920004890 Triton X-100 Polymers 0.000 description 2
239000013504 Triton X-100 Substances 0.000 description 2
125000003277 amino group Chemical group 0.000 description 2
150000001720 carbohydrates Chemical class 0.000 description 2
238000007385 chemical modification Methods 0.000 description 2
238000006243 chemical reaction Methods 0.000 description 2
229940035423 ethyl ether Drugs 0.000 description 2
239000012894 fetal calf serum Substances 0.000 description 2
239000012535 impurity Substances 0.000 description 2
238000010348 incorporation Methods 0.000 description 2
239000002502 liposome Substances 0.000 description 2
238000004949 mass spectrometry Methods 0.000 description 2
230000000051 modifying effect Effects 0.000 description 2
230000017095 negative regulation of cell growth Effects 0.000 description 2
239000003921 oil Substances 0.000 description 2
230000003389 potentiating effect Effects 0.000 description 2
238000002360 preparation method Methods 0.000 description 2
230000009145 protein modification Effects 0.000 description 2
102000004169 proteins and genes Human genes 0.000 description 2
108090000623 proteins and genes Proteins 0.000 description 2
239000011541 reaction mixture Substances 0.000 description 2
238000006485 reductive methylation reaction Methods 0.000 description 2
229960001153 serine Drugs 0.000 description 2
239000000243 solution Substances 0.000 description 2
QGVNJRROSLYGKF-UHFFFAOYSA-N thiobarbital Chemical compound CCC1(CC)C(=O)NC(=S)NC1=O QGVNJRROSLYGKF-UHFFFAOYSA-N 0.000 description 2
230000004614 tumor growth Effects 0.000 description 2
NVNPEYQWKCQBBU-ADMXJUBYSA-N (2r,4s,5r,6r)-2-[(2s,3s,4r,5r,6s)-2-[(2r,3s,4s,5s,6s)-3-acetamido-2-[(2s,3r,4s,5s,6r)-4-[(2r,4s,5r,6r)-5-amino-2-carboxy-4-hydroxy-6-(1,2,3-trihydroxypropyl)oxan-2-yl]oxy-6-[(2r,3s,4r,5r,6r)-4,5-dihydroxy-2-(hydroxymethyl)-6-[(e)-3-hydroxy-1-(octadecanoyl Chemical compound O[C@@H]1[C@@H](O)[C@H](OC(CNC(=O)CCCCCCCCCCCCCCCCC)C(O)\C=C\CCCCCCCCCCCCC)O[C@H](CO)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@]2(O[C@H]([C@H](N)[C@@H](O)C2)C(O)C(O)CO)C(O)=O)[C@H](O[C@@H]2[C@H]([C@H](O[C@@H]3[C@H]([C@H](O[C@@]4(O[C@H]([C@H](N)[C@@H](O)C4)C(O)C(O)O[C@@]4(O[C@H]([C@H](N)[C@@H](O)C4)C(O)C(O)CO)C(O)=O)C(O)=O)[C@H](O)[C@H](CO)O3)O)[C@H](O)[C@H](CO)O2)NC(C)=O)[C@H](CO)O1 NVNPEYQWKCQBBU-ADMXJUBYSA-N 0.000 description 1
MQKSCOKUMZMISB-GPWKTZPCSA-N (2s,3r,4s,5r,6r)-2-[(2r,3s,4r,5r,6r)-6-[(e,2s,3r)-2-amino-3-hydroxyoctadec-4-enoxy]-4,5-dihydroxy-2-(hydroxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound O[C@@H]1[C@@H](O)[C@H](OC[C@H](N)[C@H](O)/C=C/CCCCCCCCCCCCC)O[C@H](CO)[C@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 MQKSCOKUMZMISB-GPWKTZPCSA-N 0.000 description 1
ZKVKFPZCVMFTCI-CWFJQSRLSA-N (E,3R,4R)-3-amino-2,4-dihydroxynonadec-5-enal Chemical compound C(=O)C(O)[C@H](N)[C@H](O)\C=C\CCCCCCCCCCCCC ZKVKFPZCVMFTCI-CWFJQSRLSA-N 0.000 description 1
AFSHUZFNMVJNKX-LLWMBOQKSA-N 1,2-dioleoyl-sn-glycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](CO)OC(=O)CCCCCCC\C=C/CCCCCCCC AFSHUZFNMVJNKX-LLWMBOQKSA-N 0.000 description 1
DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 1
201000009030 Carcinoma Diseases 0.000 description 1
ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 1
229930186217 Glycolipid Natural products 0.000 description 1
108010033040 Histones Proteins 0.000 description 1
229930192392 Mitomycin Natural products 0.000 description 1
NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 1
241000187681 Nocardia sp. Species 0.000 description 1
108091000080 Phosphotransferase Proteins 0.000 description 1
102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
240000004808 Saccharomyces cerevisiae Species 0.000 description 1
229930006000 Sucrose Natural products 0.000 description 1
CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
ZKHQWZAMYRWXGA-KNYAHOBESA-N [[(2r,3s,4r,5r)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] dihydroxyphosphoryl hydrogen phosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)O[32P](O)(O)=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KNYAHOBESA-N 0.000 description 1
BLAKAEFIFWAFGH-UHFFFAOYSA-N acetyl acetate;pyridine Chemical compound C1=CC=NC=C1.CC(=O)OC(C)=O BLAKAEFIFWAFGH-UHFFFAOYSA-N 0.000 description 1
238000006640 acetylation reaction Methods 0.000 description 1
230000009471 action Effects 0.000 description 1
239000002246 antineoplastic agent Substances 0.000 description 1
ZPNFWUPYTFPOJU-MPSLMFKFSA-N aprotinin Chemical compound CC[C@H](C)[C@@H]1NC(=O)[C@@H](CCCNC(N)=N)NC(=O)[C@@H](C)NC(=O)[C@H](CCCCN)NC(=O)[C@@H]2CSSC[C@H]3NC(=O)CNC(=O)CNC(=O)[C@H](Cc4ccc(O)cc4)NC(=O)[C@H](NC(=O)[C@H](Cc4ccccc4)NC(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](CSSC[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](Cc4ccccc4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC3=O)C(=O)N[C@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](CSSC[C@@H](NC(=O)[C@H](Cc3ccccc3)NC(=O)[C@@H](CC(O)=O)NC(=O)[C@H]3CCCN3C(=O)[C@H](N)CCCNC(N)=N)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N3CCC[C@@H]3C(=O)N3CCC[C@H]3C(=O)N[C@H](Cc3ccc(O)cc3)C(=O)N[C@H]([C@H](C)O)C(=O)NCC(=O)N3CCC[C@H]3C(=O)N2)C(=O)NCC(=O)NCC(=O)N[C@H](C)C(O)=O)NC(=O)[C@@H](CC(C)C)NC(=O)CNC(=O)[C@@H](C)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](Cc2ccc(O)cc2)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@@H](Cc2ccc(O)cc2)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](NC1=O)[C@H](C)CC)[C@@H](C)O)C(C)C ZPNFWUPYTFPOJU-MPSLMFKFSA-N 0.000 description 1
IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
210000000601 blood cell Anatomy 0.000 description 1
244000309466 calf Species 0.000 description 1
201000011510 cancer Diseases 0.000 description 1
150000001783 ceramides Chemical class 0.000 description 1
239000003153 chemical reaction reagent Substances 0.000 description 1
WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
229940127089 cytotoxic agent Drugs 0.000 description 1
229940009976 deoxycholate Drugs 0.000 description 1
KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 description 1
238000010511 deprotection reaction Methods 0.000 description 1
235000014113 dietary fatty acids Nutrition 0.000 description 1
OTKJDMGTUTTYMP-UHFFFAOYSA-N dihydrosphingosine Natural products CCCCCCCCCCCCCCCC(O)C(N)CO OTKJDMGTUTTYMP-UHFFFAOYSA-N 0.000 description 1
230000007071 enzymatic hydrolysis Effects 0.000 description 1
238000006047 enzymatic hydrolysis reaction Methods 0.000 description 1
238000013213 extrapolation Methods 0.000 description 1
238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 1
229930195729 fatty acid Natural products 0.000 description 1
239000000194 fatty acid Substances 0.000 description 1
150000004665 fatty acids Chemical class 0.000 description 1
230000001605 fetal effect Effects 0.000 description 1
239000001963 growth medium Substances 0.000 description 1
238000010438 heat treatment Methods 0.000 description 1
230000007062 hydrolysis Effects 0.000 description 1
238000006460 hydrolysis reaction Methods 0.000 description 1
238000011835 investigation Methods 0.000 description 1
238000002955 isolation Methods 0.000 description 1
210000003734 kidney Anatomy 0.000 description 1
230000007246 mechanism Effects 0.000 description 1
-1 methyl iodide-sodium hydride-dimethyl-formamide Chemical compound 0.000 description 1
239000000693 micelle Substances 0.000 description 1
229960004857 mitomycin Drugs 0.000 description 1
230000004048 modification Effects 0.000 description 1
238000012986 modification Methods 0.000 description 1
YIEDSISPYKQADU-UHFFFAOYSA-N n-acetyl-n-[2-methyl-4-[(2-methylphenyl)diazenyl]phenyl]acetamide Chemical compound C1=C(C)C(N(C(C)=O)C(=O)C)=CC=C1N=NC1=CC=CC=C1C YIEDSISPYKQADU-UHFFFAOYSA-N 0.000 description 1
230000017066 negative regulation of growth Effects 0.000 description 1
210000000056 organ Anatomy 0.000 description 1
239000003960 organic solvent Substances 0.000 description 1
210000005259 peripheral blood Anatomy 0.000 description 1
239000011886 peripheral blood Substances 0.000 description 1
239000003208 petroleum Substances 0.000 description 1
102000020233 phosphotransferase Human genes 0.000 description 1
239000002244 precipitate Substances 0.000 description 1
239000000047 product Substances 0.000 description 1
238000000746 purification Methods 0.000 description 1
238000010992 reflux Methods 0.000 description 1
229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
239000011780 sodium chloride Substances 0.000 description 1
OTKJDMGTUTTYMP-ZWKOTPCHSA-N sphinganine Chemical compound CCCCCCCCCCCCCCC[C@@H](O)[C@@H](N)CO OTKJDMGTUTTYMP-ZWKOTPCHSA-N 0.000 description 1
210000000952 spleen Anatomy 0.000 description 1
108700026239 src Genes Proteins 0.000 description 1
230000000638 stimulation Effects 0.000 description 1
239000000126 substance Substances 0.000 description 1
239000005720 sucrose Substances 0.000 description 1
239000006228 supernatant Substances 0.000 description 1
229940104230 thymidine Drugs 0.000 description 1

Classifications

- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders

Landscapes

Health & Medical Sciences (AREA)
Animal Behavior & Ethology (AREA)
Life Sciences & Earth Sciences (AREA)
General Health & Medical Sciences (AREA)
Public Health (AREA)
Medicinal Chemistry (AREA)
Chemical & Material Sciences (AREA)
Veterinary Medicine (AREA)
Pharmacology & Pharmacy (AREA)
Organic Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
General Chemical & Material Sciences (AREA)
Chemical Kinetics & Catalysis (AREA)
Oncology (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Immunology (AREA)
Epidemiology (AREA)
Pain & Pain Management (AREA)
Rheumatology (AREA)
Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

CA002007507A 1989-02-03 1990-01-10 Sphingosine et n-methyl-sphingosine inhibiteurs de la croissance des cellules Expired - Fee Related CA2007507C (fr)

Applications Claiming Priority (4)

Application Number	Priority Date	Filing Date
US30637889A	1989-02-03	1989-02-03
US306,378		1989-02-03
US39013589A	1989-08-07	1989-08-07
US390,135		1989-08-07

Publications (2)

Publication Number	Publication Date
CA2007507A1 CA2007507A1 (fr)	1990-08-03
CA2007507C true CA2007507C (fr)	1998-05-19

Family

ID=26975128

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
CA002007507A Expired - Fee Related CA2007507C (fr)	1989-02-03	1990-01-10	Sphingosine et n-methyl-sphingosine inhibiteurs de la croissance des cellules

Country Status (6)

Country	Link
EP (1)	EP0381514B1 (fr)
JP (1)	JP2976055B2 (fr)
AT (1)	ATE122560T1 (fr)
CA (1)	CA2007507C (fr)
DE (1)	DE69019388T2 (fr)
DK (1)	DK0381514T3 (fr)

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US5583160A (en) *	1989-02-03	1996-12-10	The Biomembrane Institute	Methylsphingosine used to treat apoptosis
US5151360A (en) *	1990-12-31	1992-09-29	Biomembrane Institute	Effect of n,n,n-trimethylsphingosine on protein kinase-c activity, melanoma cell growth in vitro, metastatic potential in vivo and human platelet aggregation
US5260288A (en) *	1992-04-03	1993-11-09	The Biomembrane Institute	Method for inhibition of cell motility by sphingosine-1-phosphate and derivatives
IL121320A (en)	1997-02-23	2000-12-06	Ibr Ltd	Extracts from cells or tissue of organisms which are capable of entering dormancy for inhibition of proliferation of target cells or tissue
US6800661B1 (en)	1997-04-15	2004-10-05	Board Of Trustees Of The University Of Illinois	Spisulosine compounds
US6107520A (en) *	1997-04-15	2000-08-22	The Board Of Trustees Of The University Of Illinois	Spisulosine compounds
USRE38793E1 (en)	1997-04-15	2005-09-06	Rinehart Kenneth L	Spisulosine compounds
AUPO900297A0 (en) *	1997-09-08	1997-10-02	Medvet Science Pty. Ltd.	A method of modulating cellular activity
US6649362B2 (en)	1997-09-08	2003-11-18	Medvet Science Pty. Ltd.	Screening method for an agent having an effect on a sphingosine kinase signaling pathway
MXPA02007995A (es) *	2000-02-16	2003-05-23	Ruffles Graham Keith	Derivados de tetrahidrofurilo sustituidos por oxy y amino con actividad antitumoral.
EP1195604A1 (fr) *	2000-09-29	2002-04-10	Warner-Lambert Company	Procedés et compositions pour la sondage de modulateurs de lipide kinases
WO2002060405A1 (fr) *	2001-01-29	2002-08-08	Cosmoferm B.V.	Composition dermatologique veterinaire contenant une base sphingoide et/ou un derive de base sphingoide
KR100457113B1 (ko) *	2001-12-27	2004-11-16	한국원자력연구소	세라마이드류 또는 그 유도체와 다이메틸스핑고신을 유효성분으로 포함하는 방사선민감도 증진제
KR100459484B1 (ko) *	2002-05-20	2004-12-03	한국원자력연구소	엔-아세틸 파이토스핑고신과 다이메틸 파이토스핑고신을유효 성분으로 포함하는 방사선 치료 민감제 조성물
EP1426053A1 (fr) *	2002-12-03	2004-06-09	Fresenius Kabi Deutschland GmbH	Utilisation de lipides amphiphiles pour l'inhibition de métastases
ATE539741T1 (de)	2004-11-30	2012-01-15	Tno	Sphingolipide bei der behandlung und prävention von hepatischer steatose
JP2013510878A (ja) *	2009-11-12	2013-03-28	テキサステックユニバーシティー	高増殖性障害を処置する組成物および方法
TWI807411B (zh)	2017-04-27	2023-07-01	西班牙商瑪製藥股份有限公司	抗腫瘤化合物

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US4816450A (en) *	1986-09-15	1989-03-28	Duke University	Inhibition of protein kinase C by long-chain bases

1990
- 1990-01-10 CA CA002007507A patent/CA2007507C/fr not_active Expired - Fee Related
- 1990-02-02 EP EP90301099A patent/EP0381514B1/fr not_active Expired - Lifetime
- 1990-02-02 DE DE69019388T patent/DE69019388T2/de not_active Expired - Fee Related
- 1990-02-02 AT AT90301099T patent/ATE122560T1/de not_active IP Right Cessation
- 1990-02-02 DK DK90301099.9T patent/DK0381514T3/da active
- 1990-02-02 JP JP2025010A patent/JP2976055B2/ja not_active Expired - Fee Related

Also Published As

Publication number	Publication date
DE69019388D1 (de)	1995-06-22
DE69019388T2 (de)	1996-01-04
EP0381514A2 (fr)	1990-08-08
JPH03157336A (ja)	1991-07-05
CA2007507A1 (fr)	1990-08-03
JP2976055B2 (ja)	1999-11-10
EP0381514A3 (fr)	1991-07-17
EP0381514B1 (fr)	1995-05-17
ATE122560T1 (de)	1995-06-15
DK0381514T3 (da)	1995-09-04

Legal Events

Date	Code	Title	Description
1993-04-27	EEER	Examination request
2005-01-10	MKLA	Lapsed

Publication	Publication Date	Title
CA2007507C (fr)	1998-05-19	Sphingosine et n-methyl-sphingosine inhibiteurs de la croissance des cellules
US5663404A (en)	1997-09-02	Sphingosine-1-phosphate essentially free of L-threo isomer
Ladisch et al.	1994	Ceramide structure predicts tumor ganglioside immunosuppressive activity.
JPH01254623A (ja)	1989-10-11	スフインゴ糖脂質代謝の阻害剤を有効成分として含有する癌治療薬
US5369030A (en)	1994-11-29	Method of inducing cellular differentiations and altering cell phenotype using ceramide analogs
US5627171A (en)	1997-05-06	Sphingosine-1-phosphate/trimethylsphingosine composition
US5583160A (en)	1996-12-10	Methylsphingosine used to treat apoptosis
US5137919A (en)	1992-08-11	Effect of N,N,N,-trimethylsphingosine on protein kinase C activity melanoma cell growth in vitro; metastatic potential in vivo and human platelet aggregation
Delgado et al.	2012	Sphingolipid modulation: a strategy for cancer therapy
US5292765A (en)	1994-03-08	Neuroprotection by indolactam V and derivatives thereof
Magrassi et al.	1998	Vitamin D metabolites activate the sphingomyelin pathway and induce death of glioblastoma cells
US6756504B2 (en)	2004-06-29	Sphingolipids
US6031135A (en)	2000-02-29	Trimethylsphingosine derivatives
WO2001079152A1 (fr)	2001-10-25	Sphingolipides
Dany	2017	Sphingosine metabolism as a therapeutic target in cutaneous melanoma
JPH05508863A (ja)	1993-12-09	セラミドを使用して細胞分裂を誘導する方法
CA2783405A1 (fr)	2011-06-16	Composes de desoxynojirimycine n-substituee destines a l'inhibition de l'osteoclastogenese et/ou de l'activation des osteoclastes
JP4707390B2 (ja)	2011-06-22	修飾されたアシル基を有するガングリオシド
KR100459484B1 (ko)	2004-12-03	엔-아세틸 파이토스핑고신과 다이메틸 파이토스핑고신을유효 성분으로 포함하는 방사선 치료 민감제 조성물
US5330977A (en)	1994-07-19	Di-N-acetyl lysoganglioside compositions
Shier et al.	2000	Sphingosine-and ceramide-analog toxins—an update
CA2461801A1 (fr)	2003-04-03	Sphingolipides
Kim et al.	2018	Thapsigargin increases IL-2 production in T cells at nanomolar concentrations
Xu et al.	2000	Antitumour activity of sphingoid base adducts of phenethyl isothiocyanate
HK1167999A1 (en)	2012-12-21	Lysosomotropic inhibitors of acid ceramidase